title: Staphylococcus aureus alpha toxin suppresses effective innate and adaptive immune responses in a murine dermonecrosis model.
abstract: An optimal host response against Staphylococcus aureus skin and soft tissue infections (SSTI) is dependent on IL-1β and IL-17 mediated abscess formation. Alpha toxin (AT), an essential virulence factor for SSTI, has been reported to damage tissue integrity; however its effect on the immune response has not been investigated. Here, we demonstrate that infection with USA300 AT isogenic mutant (Δhla), or passive immunization with an AT neutralizing mAb, 2A3, 24 h prior to infection with wild type USA300 (WT), resulted in dermonecrotic lesion size reduction, and robust neutrophil infiltration. Infiltration correlates with increase in proinflammatory cytokines and chemokines, as well as enhanced bacterial clearance relative to immunization with a negative control mAb. In addition, infection with Δhla, or with WT +2A3, resulted in an early influx of innate IL-17(+)γδT cells and a more rapid induction of an adaptive immune response as measured by Th1 and Th17 cell recruitment at the site of infection. These results are the first direct evidence of a role for AT in subverting the innate and adaptive immune responses during a S. aureus SSTI. Further, these effects of AT can be overcome with a high affinity anti-AT mAb resulting in a reduction in disease severity.
authors.affiliation: Department of Infectious Disease, MedImmune, LLC, Gaithersburg, Maryland, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Tkaczyk
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Hamilton
authors.forename: Vivekananda
authors.initials: V
authors.lastname: Datta
authors.forename: Xiang Ping
authors.initials: XP
authors.lastname: Yang
authors.forename: Jamese J
authors.initials: JJ
authors.lastname: Hilliard
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Stephens
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Sadowska
authors.forename: Lei
authors.initials: L
authors.lastname: Hua
authors.forename: Terrence
authors.initials: T
authors.lastname: O'Day
authors.forename: JoAnn
authors.initials: J
authors.lastname: Suzich
authors.forename: Charles Kendall
authors.initials: CK
authors.lastname: Stover
authors.forename: Bret R
authors.initials: BR
authors.lastname: Sellman
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D018461:Soft Tissue Infections / Q000276:immunology / Q000382:microbiology; D013211:Staphylococcus aureus / Q000378:metabolism* / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D001427:Bacterial Toxins; D018925:Chemokines; D020381:Interleukin-17